It is known, that monoamine oxidase (MAO) is one of the main metabolizing enzyme [Blaschko H. Pharmacol. Rev. 4, 415, (1951)] of biogenic amines occurring in the human nerve cells. Due to its activity the biogenic amines, playing an essential role in neurotransmission, are decomposed into ineffective metabolites. It was recognized that in certain diseases the level of the brain biogenic amines was decreased.
Agents, which inhibit the metabolizing enzyme (enzymes) can restore the normal level of these amines. This is the reason why MAO inhibitors were introduced in the human therapy. There are observations that MAO-inhibitions may lead to a serious side effect which is connected to tyramine (structurally a biogenic amine) potentiation ("cheese reaction") which is derived from foods and may induce blood pressure increase, and can be lethal. [Piackar and co-workers, Psychopharmacology 73, 3087, (1981)].
MAO exists in two forms, termed MAO-A and MAO-B. Inhibiting the B form selectively, the A form is able to decompose tyramine, which is a mixed type of substrate and the dangerous side effect can be avoided. This selective MAO inhibition can be accomplished by administration of (-)-deprenyl, [(-)N-(-1-phenyl-isopropyl)-N-methyl-propinylamine-hydrochloride)] which selectively and irreversibly inhibits the MAO-B enzyme [Elsworth et al., Psychopharmacology 57, 33, (1978)]. Because of the irreversible inhibition, the recovery of the enzyme activity can only be due to new enzyme resynthesis.
The development of the irreversible inhibition of the enzyme involves two steps. The first one is reversible and only the formation of the second enzyme-inhibitor complex becomes irreversible. The half life of enzyme regeneration is 7-8 days. [Oreland et al., J. Neural. Transm. Suppl. 32, 55-59 (1990)].
The substrate specificities of the enzymes and the selectivity of the mostly known inhibitors are reviewed by Dostert and his co-workers. [Medicinal Research Reviews, Vol 9, No. 1. 45-89, (1989)].
Balard [Science 219, 979-980, (1980)] and Burns (Proc. Natl. Acad. Sci 80, 4546-4550 (1983)] described that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) due to its neurotoxic activity evokes parkinsonian syndrome in man and similar symptoms can be observed in animal experiments. The MPTP causes selective damage of the dopaminergic neurons to the corpus striatum. The histological alterations are similar to those, observed in postmortem parkinsonian brains. It is known, that this effect of MPTP can be prevented with MAO inhibitors, especially with deprenyl. The preventing role of (-)-deprenyl is due to the inhibition of the conversion of MPTP to MPP.sup.+, [Nature, 311, 467, (1984)]. The MPTP induced neuronal damage can be retarded also with dopamine uptake inhibitors [Proc. Natl. Acad. Sci. USA, 82, 2175, 1985] like mazindol, by inhibiting the active uptake of MPP.sup.+ (methyl-phenyl-pyridinium ion) into the dopaminergic neurons.
During the period of MAO activity hydrogen peroxide and oxygen free radicals are formed, which can lead to oxydative damage of the neurons. Ammonia and some heterocyclic isoquinolines can also be formed by the MAO which can be considered neurotoxic. [Maret et al., Drug metabolism. Reviews, 22, 291-332, (1990); P. Riederer et al., Acta Neurol. Scand. 126, 41 (1989); Benedetti and Dostert, Biochem. Pharm. Vol 38, 555, (1989)].
It is known that DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromo-benzylamine], a neurotoxic agent, induces noradrenaline (NA) depletion selectively from the central and peripheral noradrenergic neurons [Grzanna et al., J. Histochem. Cytochem., 1435-1442, (1989)].
It is further known that--reuptake inhibitors such as desipramine [10,11-Dihydro-N-methyl-5-H-dibenz(6,7)azepine-5-propanamine) inhibit the NA-depleting effect of DSP-4 [Johnsson et al., Neuroscience, 7, 2895, (1982); Ross Br. J. Pharmacol., 58, 521, (1976)]--MDL 72974A [(E)-4-fluoro-beta-fluoro-ethylene benzene butamine] a highly selective MAO-B inhibitor lacks catecholaminergic reuptake blocking properties and fails to prevent DSP-4 induced toxicity [Finnegen et al. Eru. J. of Pharmacol., 184, 119-126 (1990)].
It became clear, that (-)-deprenyl cannot be considered only as a simple selective, irreversible inhibitor of MAO-B. It was stated, that it inhibits the uptake of dopamine, noradrenaline and tyramine in the nerve terminals and into the peripheral ganglions, but only in extremely high doses [Knoll, Advances in Biochem. Psychopharmacology Vol, 5, 393,(1972)]. It must be kept in mind that, in addition to the MAO inhibitory effect deprenyl possesses an uptake inhibitory activity.
The object of the invention is to prepare a pharmaceutical composition with optimal properties for the treatment of neurodegenerative diseases.